<br>单细胞转录组学揭示了细胞对 BK 病毒感染的异质性反应,Journal of Virology

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单细胞转录组学揭示了细胞对 BK 病毒感染的异质性反应
Journal of Virology ( IF 4.0 ) Pub Date : 2021-02-24 , DOI: 10.1128/jvi.02237-20
Ping An ₁ , Paul G Cantalupo ₁ , Wenshan Zheng _{2,

3} , Maria Teresa Sáenz-Robles ₁ , Alexis M Duray ₁ , David Weitz _{2,

4,

5} , James M Pipas ₆

Affiliation

BK 病毒（BKV）是一种人类多瘤病毒，通常无害，但可在免疫抑制个体中引起毁灭性疾病。肾细胞 BKV 感染是接受免疫抑制治疗的肾移植患者的常见问题。在培养的原代人肾近端肾小管上皮（RPTE）细胞中，BKV 发生生产性感染。BKV 编码的大 T 抗原（LT）诱导细胞周期进入，导致许多与细胞增殖相关的基因上调。一致地，对大量感染细胞群进行的微阵列和转录组测序（RNA-seq）实验确定了几种被 BKV 上调的增殖相关途径。这些研究揭示了少数下调的基因。在这项研究中，我们分析了单个模拟或 BKV 感染细胞中的病毒和细胞转录物。我们发现感染细胞之间病毒 mRNA 的水平差异很大，导致 LT 和病毒衣壳蛋白表达水平不同。表达最高水平病毒转录物的细胞约占培养物的 20%，并且具有与表达较低水平病毒 mRNA 的细胞不同的基因表达模式。令人惊讶的是，表达低水平病毒 mRNA 的细胞不会随着时间的推移而发展到高表达，这表明这两种细胞反应是在感染之前或之后不久确定的。最后，将表达高水平病毒 mRNA 的细胞的细胞基因表达模式与模拟感染细胞或表达低水平病毒 mRNA 的细胞的细胞基因表达模式进行比较，揭示了以前未被发现的被 BKV 下调的途径。其中包括与药物代谢和解毒、肿瘤坏死因子（TNF）信号传导、能量代谢和翻译相关的通路。

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Single-Cell Transcriptomics Reveals a Heterogeneous Cellular Response to BK Virus Infection

BK virus (BKV) is a human polyomavirus that is generally harmless but can cause devastating disease in immunosuppressed individuals. BKV infection of renal cells is a common problem for kidney transplant patients undergoing immunosuppressive therapy. In cultured primary human renal proximal tubule epithelial (RPTE) cells, BKV undergoes a productive infection. The BKV-encoded large T antigen (LT) induces cell cycle entry, resulting in the upregulation of numerous genes associated with cell proliferation. Consistently, microarray and transcriptome sequencing (RNA-seq) experiments performed on bulk infected cell populations identified several proliferation-related pathways that are upregulated by BKV. These studies revealed few genes that are downregulated. In this study, we analyzed viral and cellular transcripts in single mock- or BKV-infected cells. We found that the levels of viral mRNAs vary widely among infected cells, resulting in different levels of LT and viral capsid protein expression. Cells expressing the highest levels of viral transcripts account for approximately 20% of the culture and have a gene expression pattern that is distinct from that of cells expressing lower levels of viral mRNAs. Surprisingly, cells expressing low levels of viral mRNA do not progress with time to high expression, suggesting that the two cellular responses are determined prior to or shortly following infection. Finally, comparison of cellular gene expression patterns of cells expressing high levels of viral mRNA with those of mock-infected cells or cells expressing low levels of viral mRNA revealed previously unidentified pathways that are downregulated by BKV. Among these are pathways associated with drug metabolism and detoxification, tumor necrosis factor (TNF) signaling, energy metabolism, and translation.

更新日期：2021-02-24

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